Drug-resistant infectious bacteria, that is, bacteria that are not killed or inhibited by existing antibacterial and antimicrobial compounds, have become an alarmingly serious worldwide health problem. Rubenstein, Science, 264, 360 (1994). It is believed that a number of bacterial infections may soon be untreatable unless alternative drug treatments are identified.
Antimicrobial or antibacterial resistance has been recognized since the introduction of penicillin nearly 50 years ago. At that time, penicillin-resistant infections caused by Staphylococcus aureus rapidly appeared. Today, hospitals worldwide are facing challenges from the rapid emergence and dissemination of microbes resistant to one or more antimicrobial and antibacterial agents commonly in use today. Several strains of antibiotic-resistant bacteria are now emerging and are becoming a threat to human and animal populations, including those summarized below:
Strains of Staphylococcus aureus resistant to methicillin and other antibiotics are endemic in hospitals. Infection with methicillin-resistant S. aureus (MRSA) strains may also be increasing in non-hospital settings. Vancomycin is the only effective treatment for MRSA infections. A particularly troubling observation is that S. aureus strains with reduced susceptibility to vancomycin have emerged recently in Japan and the United States. The emergence of vancomycin-resistant strains would present a serious problem for physicians and patients.
Increasing reliance on vancomycin has led to the emergence of vancomycin-resistant enterococci (VRE), bacteria that infect wounds, the urinary tract and other sites. Until 1989, such resistance had not been reported in U.S. hospitals. By 1993, however, more than 10 percent of hospital-acquired enterococci infections reported to the Centers for Disease Control (“CDC”) were resistant.
Streptococcus pneumoniae causes thousands of cases of meningitis and pneumonia, as well as 7 million cases of ear infection in the United States each year. Currently, about 30 percent of S. pneumoniae isolates are resistant to penicillin, the primary drug used to treat this infection. Many penicillin-resistant strains are also resistant to other antimicrobial or antibacterial drugs.
Strains of multi-drug resistant tuberculosis (MDR-TB) have emerged over the last decade and pose a particular threat to people infected with HIV. Drug-resistant strains are as contagious as those that are susceptible to drugs. MDR-TB is more difficult and vastly more expensive to treat, and patients may remain infectious longer due to inadequate treatment. Multi-drug resistant strains of Mycobacterium tuberculosis have also emerged in several countries, including the U.S.
Diarrheal diseases cause almost 3 million deaths a year, mostly in developing countries, where resistant strains of highly pathogenic bacteria such as Shigella dysenteriae, Campylobacter, Vibrio cholerae, Escherichia coli and Salmonella are emerging. Furthermore, recent outbreaks of Salmonella food poisoning have occurred in the United States. A potentially dangerous “superbug” known as Salmonella typhimurium, resistant to ampicillin, sulfa, streptomycin, tetracycline and chloramphenicol, has caused illness in Europe, Canada and the United States.
In addition to its adverse effect on public health, antimicrobial resistance contributes to higher health care costs. Treating antibiotic resistant infections often requires the use of more expensive or more toxic drugs and can result in longer hospital stays for infected patients. The Institute of Medicine, a part of the National Academy of Sciences, has estimated that the annual cost of treating antibiotic resistant infections in the United States may be as high as $30 billion.
In addition, the use of antibiotics in food animal feeds and the extent to which such use contributes to the development of drug resistance have been under recent discussion, see, e.g., C. Marwick, “Animal Feed Antibiotic Use Raises Drug Resistance Fear,” Journal of the American Medical Association, 282(2):120-2, Jul. 14, 1999, and T. R. Shryock, “Relationship between usage of antibiotics in food-producing animals and the appearance of antibiotic resistant bacteria,” International Journal of Antimicrobial Agents, 12(4):275-8, August 1999. The use of antibiotics as well as biocides can lead to antibiotic or drug-resistant organisms, see, e.g., A. D. Russel, “Mechanisms of bacterial resistance to antibiotics and biocides,” Progress in Medicinal Chemistry, 35:133-97, 1998.
Further, spore-forming bacteria can be lethal. For example, Bacillus anthracis causes the deadly disease, anthrax. There exists an uncertainty relating to the efficacy of currently available vaccines against B. anthracis. Further, there is a likelihood that terrorists could employ antibiotic-resistant strains, e.g., engineered strains that are not recognized by B. anthracis antibodies or common bacteria engineered to carry the virulence gene (see, e.g., T. C. Dixon et al., “Anthrax,” New England Journal of Medicine, 341 (11), 815-826, September 1999). The foregoing shows that there exists a need for a novel treatment against spore-forming bacteria, particularly B. anthracis or bacteria carrying the virulence gene of B. anthracis. 
Further, the incidence of serious fungal infections, either systemic or topical, continues to increase for plants, animals, and humans. Fungi are plant-like eukaryotes that grow in colonies of single cells, called yeasts, or in filamentous multicellular aggregates, called molds. While many fungi are common in the environment and not harmful to plants or mammals, some are parasites of terrestrial plants and others can produce disease in humans and animals. When present in humans, mycotic (fungal) diseases can include contagious skin and hair infections, noncontagious systemic infections, and noncontagious foodborne toxemias. The incidence of such infections is not insignificant; in the U.S. approximately 10% of the population suffers from contagious skin and hair infections. While few healthy persons develop life-threatening systemic fungal infections, immunocompromised individuals, such as found in pregnancy, congenital thymic defects, or acquired immune deficiency syndrome (AIDS), can become seriously ill. This is further illustrated by the fact that fungal infections have become a major cause of death in organ transplant recipients and cancer patients.
Numerous antifungal agents have been developed for topical use against nonsystemic fungal infections. However, the treatment of systemic fungal infections, particularly in immunocrompromised hosts, continues to be a major objective in infectious disease chemotherapy. The organisms most commonly implicated in systemic infections include Candida spp., Cryptococcus neoformans, and Aspergillus spp., although there are a number of emerging pathogens. The major classes of systemic drugs in use currently are the polyenes (e.g., amphotericin B) and the azoles (e.g., fluconazole). While somewhat effective in otherwise healthy patients, these agents are inadequate in severely immunocompromised individuals. Furthermore, drug resistance has become a serious problem, rendering these antifungal agents ineffective in some individuals.
One reason for the limited number of systemic antifungal agents relates to the fact that, unlike bacteria, which are prokaryotes, yeast and molds are eukaryotes. Thus the biochemical make-up of yeast and molds more closely resembles eukaryotic human and animal cells. In general, this has made it difficult to develop antifungal drugs which selectively target in yeast or mold an essential enzyme or biochemical pathway that has a close analog in humans and animals.
In addition, in view of the risks such as toxicity or carcinogenicity associated with many common pesticides, fungicides, or bactericides, new approaches are needed to control pests, or insects in the environment, as well as microbial diseases in plants and food crops, see, e.g., D. W. Wong and G. H. Robertson, “Combinatorial chemistry and its applications in agriculture and food,” Advances in Experimental Medicine & Biology, 464:91-105, 1999, and S. H. Zahm and M. H. Ward, “Pesticides and childhood cancer,” Environmental Health Perspectives, 106, Suppl. 3:893-908, June 1998.
Bioterrorism, especially agricultural bioterrorism (or agroterrorism), is presently of great concern in this country as well as in many countries throughout the world. See, e.g., Joseph W. Foxell, Jr., “Current Trends in Agroterrorism (Antilivestock, Anticrop, and Antisoil Bioagricultural Terrorism) and Their Potential Impact on Food Security”, in Studies in Conflict & Terrorism, 24, 107-129 (2001); Mark Wheelis, “Agricultural Biowarfare and Bioterrorism—An Analytical Framework and Recommendations for the Fifth BTWC Review Conference”, 14th Workshop of the Pugwash Study Group on the Implementation of the Chemical Biological Weapons Conventions, Geneva, Switzerland, November 2000; Radford G. David, “Agricultural Bioterrorism—New Frontiers” in Biowarfare, October 2001; Robert P. Kadlec, Chapter 10, Biological Weapons for Waging Economic Warfare, Battle of the Future, 21st Century Warfare Issues, Aerospace Power Chronicles; Senator Kay Bailey Hutchison, S. 1563, The Agricultural Bioterrorism Countermeasures Act of 2001, Senate Floor Speech, Oct. 17, 2001, page S. 10796.
Given the above, there exists a need to develop novel antimicrobial agents, especially those which act by different mechanisms than those agents in use currently. There exists a need to develop antibacterial agents that preferentially attack microorganisms and kill or deactivate the harmful organism without causing any attendant undesirable side effects in a human or animal patient.
There also exists a need for methods of treating or preventing microbial infection, methods for treating an environment, methods for treating food crops and animals, methods for decontaminating objects, and/or developing countermeasures against bioterrorism, particularly agrobioterrorism.
The advantages of the present invention as well as inventive features will be apparent from the description below.